Ketogenic diet in patients with Lennox–Gastaut syndrome

PurposeThe ketogenic diet (KD) has been used as an alternative to antiepileptic drugs (AEDs) for patients with refractory epilepsy. Lennox–Gastaut syndrome (LGS) belongs to the group of epileptic encephalopathies that often prove refractory to AED treatment.In this prospective study we assess the efficacy and tolerability of the KD in patients with LGS.MethodsBetween March 1, 1990 and April 1, 2013, 61 patients who met diagnostic criteria of LGS were seen at our department. Twenty of them were placed on the KD and followed for a minimum of 16 months.ResultsThe children had previously received a mean of 6.5 different AEDs and were on a mean of 2.5 AEDs when the diet was started. Eighteen months after initiating the diet, fifteen of the initial patients (75%) remained on the diet; three patients (15%) were seizure free, three (15%) had a 75–99% decrease in seizures, two (10%) had a 50–74% decrease in seizures, and the remaining seven children (35%) had a <50% decrease in seizures. Three seizure-free patients were tapered off the diet after remaining seizure free. In the three patients who had a 75–99% decrease in seizures AEDs were reduced.ConclusionThe KD is an effective and well-tolerated treatment option for patients with LGS, not only for those with cryptogenic, but also for those with structural LGS. The diet should be considered early in the course of this syndrome.     

Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation

IntroductionPitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy.Case reportThe patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy.ConclusionsTo our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.     

Ketogenic diet as a successful early treatment modality for SCN2A mutation

SCN2A mutations have been described in a very broad spectrum of clinical phenotypes including benign (familial) neonatal/infantile seizures and early infantile epileptic encephalopathies (EIEE) as Ohtahara syndrome (OS), Dravet syndrome (DS), epilepsy of infancy with migrating focal seizures and West syndrome (WS). Treatment modalities for epilepsy caused by SCN2A mutations mainly consist of sodium channel blockers but ketogenic diet (KD) is also considered as an option of treatment for intractible seizures caused by SCN2A mutations. Because of the wide nature of the heterogeneity of mutations related to SCN2A gene, the clinical phenotypes vary in severity and treatment response to KD has been reported to be controversial.We present a patient diagnosed with OS associated with a novel SCN2A mutation (c.408G?>?A, p.Met136lle; OMIM®: 182390) who had a complete resolution of seizures and EEG abnormalities with KD commenced at 39?days of age.As far as we are aware our case is the youngest patient with SCN2A mutation treated with KD with complete resolution of epilepsy at an early age and has been seizure free of antiepileptic medications for a long duration.     

Glucose transporter type 1 deficiency: Ketogenic diet in three patients with atypical phenotype

Glucose transporter type I deficiency syndrome (GLUT-1 DS) is an inborn error of glucose transport characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia. Diagnosis is based on the finding of low cerebrospinal fluid glucose, in the absence of hypoglycemia, and identification of GLUT-1 gene mutation on chromosome 1. The classic phenotype is a severe form of early onset epileptic encephalopathy, but patient with different clinical presentation have been reported expanding the clinical spectrum. In particular, many patients show a prominent movement disorder other than epilepsy. It is known that this disease represents a treatable condition and ketogenic diet (KD) is the elective treatment in GLUT-1 DS patients. We report on KD in three unrelated Italian GLUT-1 DS female patients, diagnosed in early adulthood, all presenting with an atypical phenotype. Preliminary results seem to demonstrate efficacy of KD on paroxysmal movement disorder while positive effect on cognitive impairment result less evident.     

Clinical features of early myoclonic encephalopathy caused by a CDKL5 mutation

BackgroundCDKL5 deficiency is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene and clinically manifests often in females as drug-resistant intractable epilepsy and severe psychomotor retardation.Case reportWe report the case of a girl with a CDKL5 mutation born at 39 weeks without neonatal asphyxia. She developed epilepsy at age 1 month with myoclonus of the face and limbs, and non-rhythmic and irregular opsoclonus. She developed tonic seizures and epileptic spasms at 6 months of age and was diagnosed with symptomatic West syndrome and underwent adrenocorticotropic hormone therapy but her seizures were refractory. At the age of 4, she was introduced to our hospital and development was at 2 months of age. We diagnosed her with early myoclonic encephalopathy (EME) due to the remaining suppression-burst pattern observed on an electroencephalogram and her symptoms since onset were mainly myoclonus. At 14 years of age, mutational analysis revealed a CDKL5 mutation (c.380A > G:p.His127Arg). She was diagnosed with epileptic encephalopathy exhibiting clinical features of early myoclonic epilepsy caused by CDKL5 deficiency.ConclusionsEarly onset epilepsy with severe psychomotor retardation without a known etiology may be caused by a mutation in CDKL5. More research investigating a genotype-phenotype correlation of CDKL5 mutations is necessary because clinical severity may be associated with the location and type of mutations.     

GLUT1 deficiency syndrome 2013: Current state of the art

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is the result of impaired glucose transport into the brain. The “classic” GLUT1DS patient presents with infantile seizures (resistant to traditional seizure medications), developmental delay, acquired microcephaly, hypotonia, spasticity, and a complex movement disorder consisting of ataxia and dystonia. However, over the years, other clinical manifestations have been described, such as paroxysmal exertion-induced dystonia with or without seizures, choreoathetosis, alternating hemiplegia, and other paroxysmal events, such as intermittent ataxia, dystonia, and migraine.At the current state of the art in understanding of GLUT1DS, classifying the disease phenotype as “classical” or “non-classical” seems to be of limited clinical utility. It seems more appropriate to think in terms of a broad clinical spectrum in which we can observe intellectual impairment, acquired microcephaly, epilepsy, and movement disorders characterized by different clinical manifestations and degrees of severity.Lumbar puncture, a simple investigation, should be considered the first diagnostic step that, moreover, is feasible worldwide. Thereafter, mutational analysis of the solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) gene should be performed in patients with highly suggestive clinical findings and low cerebrospinal fluid glucose (<50 mg/dl or ratio <0.60).Early diagnosis is critical because it allows prompt initiation of treatment with a ketogenic diet (KD). Childhood is the critical period for treatment of GLUT1DS: early diagnosis is crucial for an effective etiological therapy. KD treatment can be useful in adulthood too. Compliance has been found to be much better in GLUT1DS than in the other conditions for which KD treatment is indicated.     

Long-term follow-up of the ketogenic diet for refractory epilepsy: Multicenter Argentinean experience in 216 pediatric patients

Purpose

In this Argentinean retrospective, collaborative, multicenter study, we examine the efficacy and tolerability of the ketogenic diet (KD) for different epilepsy syndromes.

Materials and methods

we evaluated the clinical records of 216 patients started on the KD between March 1, 1990 and December 31, 2010.

Results

One hundred forty of the initial patients (65%) remained on the diet at the end of the study period. Twenty-nine patients (20.5%) became seizure free and 50 children (36%) had a 75–99% decrease in seizures. Thus, 56.5% of the patients had a seizure control of more than 75%. The best results were found in patients with epilepsy with myoclonic-astatic seizures, Lennox–Gastaut syndrome, and West syndrome. Good results were also found in patients with Dravet syndrome, in those with symptomatic focal epilepsy secondary to malformations of cortical development, and in patients with tuberous sclerosis. Seizures were significantly reduced in four patients with fever-induced refractory epileptic encephalopathy in school-age children and in two patients with epileptic encephalopathy with continuous spikes and waves during slow sleep. The median period of follow-up after discontinuation of the diet was 6 years. Twenty patients who had become seizure free discontinued the diet, but seizures recurred in five (25%). Of 40 patients with a seizure reduction of more than 50% who discontinued the diet, 10 presented with recurrent seizures.

Conclusion

The ketogenic diet is a good option in the treatment of refractory epilepsy. After discontinuing the diet, seizures recurrence occurred in few patients.     

A study of 63 cases with eyelid myoclonia with or without absences: Type of seizure or an epileptic syndrome?

PurposeEyelid myoclonia and absences (EMA) induced by eye closure associated with brief, fast, and generalized paroxysms of polyspikes and waves was considered as an epileptic syndrome and a type of seizure as well. We analyzed the electroclinical features and evolution of EMA, and tried to determine if it represents a well-defined epileptic syndrome or a non-specific condition associated to other epilepsies.MethodsBetween June 1994 and June 2005, 63 patients who met diagnostic criteria of EMA were enrolled in the study and have been followed up to the present time.ResultsTwo main groups could be identified. The first group was divided into two subgroups. One subgroup of 28 patients presented EMA associated with infrequent generalized tonic–clonic seizures (GTCS), and the other 1 of 9 patients presented early-onset EMA refractory to antiepileptic drugs (AEDs), associated or not with GTCS and mental retardation. Four of them had self-induced seizures. The second group included 26 patients with EMA associated with GTCS and/or massive myoclonias, or GTCS induced by intermittent photic stimulation. All these patients had electroclinical features compatible with idiopathic generalized epilepsies.ConclusionIn the first group, EMA should be considered as a photosensitive idiopathic epileptic syndrome. A subgroup of early-onset of EMA refractory to AEDs, associated or not with GTCS and mental retardation should also be considered as a variant or a distinct photosensitive idiopathic epileptic syndrome. Finally, in the second group EMA may correspond to a type of seizures in idiopathic generalized epilepsies.     

Acquired Microcephaly in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Because of an Interstitial 3q22.3q23 Deletion

BackgroundBlepharophimosis-ptosis-epicanthus inversus syndrome is an autosomal dominant condition because of mutations or deletions of the FOXL2 gene. Microcephaly is not associated with FOXL2 mutations but has been reported in individuals with chromosome 3q deletions, which include the FOXL2 gene and other contiguous genes. The ATR gene has been reported as a candidate gene for microcephaly in individuals with contiguous deletion of chromosome 3q involving the FOXL2 gene.PatientWe describe a girl with blepharophimosis-ptosis-epicanthus inversus syndrome along with acquired microcephaly and intellectual disability.ResultsOur patient had a deletion of chromosome 3q22.2q23, which does not include the ATR gene but does include the PIK3CB gene as a candidate gene for microcephaly.ConclusionWe propose that the PIK3CB gene included in our patient's chromosome 3q deletion may be the gene responsible for microcephaly and other patients with blepharophimosis-ptosis-epicanthus inversus syndrome because of a chromosome 3q deletion.     

A case of early myoclonic encephalopathy with intractable seizures successfully treated with high-dose phenobarbital

BackgroundEarly myoclonic encephalopathy (EME) is an epileptic syndrome that develops in neonates, commonly within 1 month of birth. The condition is characterized by irregular, partial, and asynchronous myoclonus. The seizures in EME are generally refractory to antiepileptic drugs and no effective treatment for EME has been established. We encountered a case of EME in which oral high-dose phenobarbital therapy effectively alleviated seizures.Case reportA male infant developed erratic myoclonus in the face and limbs, exhibited upward gaze and facial flushing 20–30 times a day since 1 week of age. Electroencephalogram (EEG) showed a burst-suppression pattern, and considering the clinical features, EME was diagnosed. Valproate and vitamin B6 treatments were initiated; however, they were not effective. At day 58 after birth, oral high-dose phenobarbital therapy was introduced which resulted in the suppression of seizures to one or two per week and disappearance of the burst-suppression pattern on EEG.ConclusionOral high-dose phenobarbital treatment may be suitable for controlling seizures in EME.     

Partial seizures during ACTH therapy in a cryptogenic West syndrome patient

Background: Partial seizures often develop during the clinical course of infantile spasms. Herein, we report a boy with cryptogenic West syndrome, who developed partial seizures that we suspected were induced by the ACTH therapy. Subject: The patient developed cryptogenic West syndrome at six months of age and ACTH therapy was started. On the tenth day of treatment, he developed frequent partial seizures, characterized by being motionless during the seizure with eye deviation to the right. The partial seizures stopped after the ACTH was discontinued, although oral carbamazepine was commenced at the same time. Thus, a definitive role for carbamazepine in the treatment of the partial seizures was unclear as the timing of the seizure cessation also corresponded to the discontinuation of the ACTH therapy. We suspected that the partial seizures were induced by the ACTH therapy for the following reasons: (1) seizures appeared only during ACTH therapy, (2) no new epileptic focus was revealed by EEG, MRI, or ^99mTcECD SPECT, and (3) the seizures were different from the epileptic spasms. Conclusion: Our results suggest that ACTH might induce partial seizures in West syndrome. Further studies are required to confirm this phenomenon.     

Quinidine therapy for West syndrome with KCNTI mutation: A case report

The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5 months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2 years and 6 months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.     

Clonic seizures,continuous spikes-and-waves during slow sleep,choreoathetosis and response to sulthiame in a child with FRRS1L encephalopathy

BackgroundFerric chelate reductase 1 like (FRRS1L) encephalopathy is a rare cause of developmental and epileptic encephalopathy. Only a few cases have been reported thus far and seizures tend to be drug refractory. We report an additional case to highlight the good seizure response to sulthiame.Case reportA boy from non-consanguineous parents presented with history of ‘abnormal movements’ from 7 months of age. At one year of age, video electroencephalogram (EEG) monitoring demonstrated the ‘abnormal movements’ to be clonic seizures. Valproate, lamotrigine and clobazam combination were only partially effective at reducing the seizures. Repeat EEG at 1 year 8 months old revealed a continuous spikes-and-waves during slow sleep (CSWS) pattern, prompting a trial of sulthiame. After 2 weeks of sulthiame, seizures ceased completely. The clonic seizures recurred at age 4 years when sulthiame supply was interrupted, but the seizures promptly remitted following sulthiame’s resumption. Subtle choreiform movements appeared from age one year and later became more prominent. Whole exome sequencing (WES) identified a homozygous novel variant (nonsense) in the FRRS1L gene (NM_014334.3: c.670C>T:p.Gln224*). He has been seizure free since 4 years of age but remained profoundly delayed.ConclusionSulthiame may have a role in the early treatment of seizures in children with refractory epilepsy due to FRRS1L mutation.     

De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum

BackgroundHeterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 protein, an essential subunit of the DNA-dependent RNA polymerase II.Case presentationWe investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks.ConclusionThis case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.     

Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination

A girl with cardio-facio-cutaneous (CFC) syndrome due to a BRAF gene mutation (c.1454T→C, p.L485S) experienced repetitive epileptic spasms at the corrected age of 4 months. Electroencephalograms revealed hypsarrhythmia, and magnetic resonance imaging identified delayed myelination and a hypoplastic corpus callosum. Various antiepileptic treatments, including adrenocorticotropic hormone therapy, were ineffective, although transient seizure control was achieved by a ketogenic diet and clorazepate dipotassium. However, seizures with epileptic foci at the bilateral posterior temporal areas re-aggravated and remained intractable; severe psychomotor delay persisted. This case indicated that infantile spasms in CFC syndrome can be difficult to control and may be accompanied by severe psychomotor retardation and abnormal myelination.     

Does lacosamide aggravate Lennox–Gastaut syndrome? Report on three consecutive cases

Lennox–Gastaut syndrome is an intractable epileptic encephalopathy, with most patients experiencing daily seizures despite therapy with multiple antiepileptic drugs. New treatments need to be tested to define their efficacy in this syndrome. Lacosamide is a new antiepileptic drug recently approved for the treatment of partial-onset seizures. We describe three patients with Lennox–Gastaut syndrome resistant to conventional antiepileptic drugs whose seizures were aggravated by lacosamide.     

Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum

BackgroundPyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6′ carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported.Methods and ResultsWe present a phenotypic spectrum of antiquitin deficiency based on a literature review (2006 to 2015) of reports (n = 49) describing the clinical presentation of confirmed patients (n > 200) and a further six patient vignettes. Possible presentations include perinatal asphyxia; neonatal withdrawal syndrome; sepsis; enterocolitis; hypoglycemia; neuroimaging abnormalities (corpus callosum and cerebellar abnormalities, hemorrhage, white matter lesions); biochemical abnormalities (lactic acidosis, electrolyte disturbances, neurotransmitter abnormalities); and seizure response to pyridoxine, pyridoxal-phosphate, and folinic acid dietary interventions.DiscussionThe phenotypic spectrum of pyridoxine-dependent epilepsy is wide, including a myriad of neurological and systemic symptoms. Its hallmark feature is refractory seizures during the first year of life. Given its amenability to treatment with lysine-lowering strategies in addition to pyridoxine supplementation for optimal seizure control and developmental outcomes, early diagnosis of pyridoxine-dependent epilepsy is essential. All infants presenting with unexplained seizures should be screened for antiquitin deficiency by determination of α-aminoadipic semialdehyde/pyrroline 6′ carboxylate (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis.     

Developmental and epileptic encephalopathy in a young Italian woman with a de novo missense variant in the CLCN4 gene: A case report

IntroductionRaynaud-Claes syndrome is a very rare X-linked condition, characterized by intellectual disability, impaired language development, brain abnormalities, facial dysmorphisms and drug-resistant epilepsy. It is caused by loss-of-function variants in the CLCN4 gene, which encodes the 2Cl−/H + exchanger ClC-4, prominently expressed in the hippocampus and cerebellum. Different genotypic variants have been described, each exhibiting specific phenotypic characteristics. The loss-of-function variant p.Gly544Arg in the CLCN4 gene has been described in only two male probands, but there are no reports on phenotypic characterization in females.Case presentationWe present a 30-year-old Italian woman with early-onset drug-resistant epilepsy, developmental and epileptic encephalopathy, developmental delay, absence of verbal language development, behavioral impairment with autistic features, and clusters of seizures during catamenial periods. The interictal EEG showed slight inconstant slowing of the background rhythm, with abnormal frontal predominant mu like rhythm and generalized spike and polyspike wave discharges, which increased in frequency during drowsiness. A brain MRI showed slight cranio-encephalic asymmetry and a smaller size of the left hippocampus. The whole exome sequencing (WES) revealed a de novo heterozygous c.1630G > A variant in the CLCN4 gene, resulting in the amino acid substitution p.Gly544Arg (rs587777161), consistent with Raynaud-Claes syndrome.Discussion and conclusionOur patient is the first case of a de novo p.Gly544Arg variant of the CLCN4 gene in a female proband, confirming that female patients with Raynaud-Claes syndrome can be as severely affected as the male counterparts. Our case expands the phenotypic characterization of different genotypic CLCN4 variants, which can become crucial in the future for early diagnosis if targeted therapy becomes available.     

Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes

PurposeTo establish whether the disability in benign epilepsy with centrotemporal spikes (BECTS) is the result of the number of seizures, the anti-epileptic therapy or is an inherent characteristic of the syndrome itself.MethodsThirty-six children with BECTS were tested for cognitive functions prior to commencing treatment with anti-epileptic drugs, and the findings were compared with those in 15 children with normal electroencephalograms, performed for unrelated reasons. The data in the study group were further correlated with the laterality of the epileptic focus and the number of seizures.ResultsScores for verbal functioning on neuropsychological tests were significantly lower in the study group than the control group. There was no relationship between the neuropsychological scores in the patients and either lateralization of the epileptic focus or number of seizures.DiscussionChildren with BECTS have an impaired ability to process verbal information. The deficiency is apparently a result of the pathological electrical discharges that are part of the syndrome and are not dependent on the epileptic focus laterality, the number of seizures, or the anti-epileptic treatment.